Project Summary Smoking causes myriad diseases and ~500,000 deaths in the United States each year, including one-third of all cancer deaths. Nicotine is the chief agent in tobacco responsible for continued smoking. Emerging products such as e-cigarettes allow smokers to self-administer nicotine in a variety of forms and on a continuum of harm. The FDA has outlined a new two-pronged approach focusing on regulating nicotine per se. The goal of this research is to understand the potential impact of these two new FDA strategies: 1) to ensure the availability of safer alternative nicotine delivery systems (ANDS), and 2) to reduce the nicotine content in combustible cigarettes to non-addictive levels. Specifically, we will examine how well e-cigarettes and very low nicotine cigarettes (VLNCs) can substitute for combustible cigarettes in real-world settings and whether this is influenced by steady-state nicotine from a nicotine patch. For this mixed design study, 180 daily adult smokers who are not planning to quit smoking will be randomly assigned to one of three levels of the between-subjects factor: 1) VLNCs; 2) Juul e-cigarettes; or 3) no alternative product. During two different weeks, participants will be asked to switch from their usual cigarettes and use only study products. They will also be asked to use either an active nicotine or placebo patch (the within-subjects factor), provided in double-blind fashion and counterbalanced order. Participants will record each time they use their own cigarettes or any alternative product, in real time via a smartphone, and, for some use events, answer questions about the use context (e.g., affect, smoking permitted) and possible mechanisms driving use behavior (e.g., withdrawal alleviation, satisfaction, taste). We will also examine the impact of person factors such as sex, dependence, and psychiatric comorbidity and risk perceptions on use behavior. This research will provide critical information regarding the impact of cigarettes with non-addictive levels of nicotine and ANDS, with or without nicotine replacement, in real-world settings on smokers' use of their usual cigarettes and other outcomes. These data could inform regulatory policy decisions regarding the potential public health impact of ANDS and non- addictive cigarettes.